rs2305035

chr3-105720182-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The NM_170662.5(CBLB):c.1272C>T(p.Asp424=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.219 in 1,612,752 control chromosomes in the GnomAD database, including 39,798 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.21 (3630 hom., cov: 31)
  • Exomes 𝑓: 0.22 (36168 hom.)
• Consequence: CBLB NM_170662.5 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.160

Genes affected

CBLB (HGNC:1542): (Cbl proto-oncogene B) This gene encodes an E3 ubiquitin-protein ligase which promotes proteosome-mediated protein degradation by transferring ubiquitin from an E2 ubiquitin-conjugating enzyme to a substrate. The encoded protein is involved in the regulation of immune response by limiting T-cell receptor, B-cell receptor, and high affinity immunoglobulin epsilon receptor activation. Studies in mouse suggest that this gene is involved in antifungal host defense and that its inhibition leads to increased fungal killing. Manipulation of this gene may be beneficial in implementing immunotherapies for a variety of conditions, including cancer, autoimmune diseases, allergies, and infections. [provided by RefSeq, Sep 2017]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 3-105720182-G-A is Benign according to our data. Variant chr3-105720182-G-A is described in ClinVar as [Benign]. Clinvar id is 3055764.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.16 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.251 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CBLB	NM_170662.5	c.1272C>T	p.Asp424=	synonymous_variant	10/19	ENST00000394030.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CBLB	ENST00000394030.8	c.1272C>T	p.Asp424=	synonymous_variant	10/19	1	NM_170662.5	P1

Frequencies

GnomAD3 genomes AF: 0.215 AC: 32599 AN: 151802 Hom.: 3625 Cov.: 31

Gnomad AFR AF: 0.189

Gnomad AMI AF: 0.242

Gnomad AMR AF: 0.257

Gnomad ASJ AF: 0.143

Gnomad EAS AF: 0.234

Gnomad SAS AF: 0.147

Gnomad FIN AF: 0.271

Gnomad MID AF: 0.158

Gnomad NFE AF: 0.220

Gnomad OTH AF: 0.190

GnomAD3 exomes AF: 0.225 AC: 56304 AN: 250508 Hom.: 6728 AF XY: 0.218 AC XY: 29535 AN XY: 135400

Gnomad AFR exome AF: 0.189

Gnomad AMR exome AF: 0.323

Gnomad ASJ exome AF: 0.144

Gnomad EAS exome AF: 0.235

Gnomad SAS exome AF: 0.142

Gnomad FIN exome AF: 0.274

Gnomad NFE exome AF: 0.219

Gnomad OTH exome AF: 0.212

GnomAD4 exome AF: 0.219 AC: 320188 AN: 1460832 Hom.: 36168 Cov.: 34 AF XY: 0.217 AC XY: 157441 AN XY: 726750

Gnomad4 AFR exome AF: 0.195

Gnomad4 AMR exome AF: 0.316

Gnomad4 ASJ exome AF: 0.141

Gnomad4 EAS exome AF: 0.230

Gnomad4 SAS exome AF: 0.145

Gnomad4 FIN exome AF: 0.274

Gnomad4 NFE exome AF: 0.221

Gnomad4 OTH exome AF: 0.215

GnomAD4 genome AF: 0.215 AC: 32623 AN: 151920 Hom.: 3630 Cov.: 31 AF XY: 0.217 AC XY: 16136 AN XY: 74208

Gnomad4 AFR AF: 0.189

Gnomad4 AMR AF: 0.257

Gnomad4 ASJ AF: 0.143

Gnomad4 EAS AF: 0.234

Gnomad4 SAS AF: 0.148

Gnomad4 FIN AF: 0.271

Gnomad4 NFE AF: 0.220

Gnomad4 OTH AF: 0.190

Alfa AF: 0.213 Hom.: 5890

Bravo AF: 0.215

Asia WGS AF: 0.169 AC: 588 AN: 3478

EpiCase AF: 0.215

EpiControl AF: 0.205

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

CBLB-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 06, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
Cadd	Benign	6.5
Dann	Benign	0.55

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2305035; hg19: chr3-105439026; COSMIC: COSV51421248;